title: The COX-2 selective blocker etodolac inhibits TNFα-induced apoptosis in isolated rabbit articular chondrocytes.
abstract: Chondrocyte apoptosis contributes to the disruption of cartilage integrity in osteoarthritis (OA). Recently, we reported that activation of volume-sensitive Cl- current (ICl,vol) mediates cell shrinkage, triggering apoptosis in rabbit articular chondrocytes. A cyclooxygenase (COX) blocker is frequently used for the treatment of OA. In the present study, we examined in vitro effects of selective blockers of COX on the TNFα-induced activation of ICl,vol in rabbit chondrocytes using the patch-clamp technique. Exposure of isolated chondrocytes to TNFα resulted in an obvious increase in membrane Cl- conductance. The TNFα-evoked Cl- current exhibited electrophysiological and pharmacological properties similar to those of ICl,vol. Pretreatment of cells with selective COX-2 blocker etodolac markedly inhibited ICl,vol activation by TNFα as well as subsequent apoptotic events such as apoptotic cell volume decrease (AVD) and elevation of caspase-3/7 activity. In contrast, a COX-1 blocker had no effect on the decrease in cell volume or the increase in caspase-3/7 activity induced by TNFα. Thus, the COX-2-selective blocker had an inhibitory effect on TNFα-induced apoptotic events, which suggests that this drug would have efficacy for the treatment of OA.
authors.affiliation: Department of Orthopaedic Surgery, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan. kumamp@belle.shiga-med.ac.jp.
authors.forename: Kousuke
authors.initials: K
authors.lastname: Kumagai
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Kubo
authors.forename: Shinji
authors.initials: S
authors.lastname: Imai
authors.forename: Futoshi
authors.initials: F
authors.lastname: Toyoda
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Maeda
authors.forename: Noriaki
authors.initials: N
authors.lastname: Okumura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuura
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Matsusue
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D008297:Male; D011817:Rabbits; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D002712:Chlorides; D052246:Cyclooxygenase 2 Inhibitors; D014409:Tumor Necrosis Factor-alpha; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D053148:Caspase 3; D053179:Caspase 7